A number of acyclic nucleoside phosphonates have been identified as potent inhibitors of viral DNA synthesis. For hydrophilic acyclic nucleoside phosphonates to be effective antiviral drugs, the prodrugs of acyclic nucleoside phosphonates are used clinically. The current prodrugs of acyclic nucleoside phosphonates can enhance absorption and bioavailability of acyclic nucleoside phosphonates, but provide little benefits in cellular uptake because acyclic nucleoside phosphonates are liberated from the prodrugs before they enter the blood stream. A high concentration of acyclic nucleoside phosphonates in the blood will be excreted by the kidney, which imposes a potential toxicity to the organ. The objective of this proposal is to identify novel prodrugs of acyclic nucleoside phosphonates, which should aid not only drug absorption, but also cellular uptake. When the objective is realized, the dose of the new prodrugs can be greatly reduced in order to achieve the same clinical benefits as the current prodrugs. Consequently, the burden on the kidney for elimination of acyclic nucleoside phosphonates will be dramatically reduced. The ultimate goal of this proposal is to apply the improved prodrug approach to a variety of acyclic nucleoside phosphonates and to provide more effective and safer antiviral drugs. Acyclic nucleoside phosphonates having a broad-spectrum activitiy will be employed in this proposed project, and their prodrugs will be evaluated for antiviral activities against HIV and HBV viruses.